See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. Hepatitis B virus (HBV) infects more than 2 billion people alive today and is responsible for over 1 million deaths caused by acute and chronic hepatitis and hepatocellular carcinoma every year. Although remarkable progress has been made in understanding the natural history and pathogenesis of HBV infection, effective treatment and eradication of chronic HBV infection remain a tremendous therapeutic challenge. The next biomedical breakthrough towards a cure is awaiting innovative interdisciplinary approaches to examine the detailed mechanism responsible for HBV infection and replication from a molecular perspective. The planned research introduces novel molecular modeling methods combined with in vitro X-ray/neutron scattering experiments to quantify the internal structure of HBV nucleocapsids and electrostatic regulation at various stages of the viral replication. Specific aims include: 1) To determine the density distributions of the genomic nucleic acids and the C-terminal domain (CTD) of the core protein and their potential changes during NC maturation;2) To elucidate the effect of electrostatic interactions and the CTD phosphorylation state on NC maturation and stability. Theory and experiment will create a synergy because, on the one hand, the scattering experiments provide necessary data for calibration of theoretical predictions and, on the other hand, computational results will further understanding the genome packaging in greater details. Theoretical calculations will also provide information not directly accessible by scattering experiments such as structural and thermodynamic properties pertaining to capsid formation and stability in vivo. By investigating biomolecular interactions within HBV nucleocapsids that underpin the viral replication, accomplishments from this work will help to develop unconventional system-based therapeutics to regulate and ultimately eradicate HBV replication. If successful, the generic nature of the proposed computational and experimental methods ensures that this research will have unusually high impact in understanding the molecular basis of viral morphogenesis and in developing drugs for effective treatment of virus-induced contagious diseases. PERFORMANCE SITE(S) (organization, city, state) 1. University of California, Riverside 2. Pennsylvania State University College of Medicine, Hershey, PA 3. Los Alamos National Laboratory PUBLIC HEALTH RELEVANCE: This exploratory research aims to establish computational means for understanding non-specific biomolecular interactions within Hepatitis B virus (HBV) nucleocapsids that underpin the internal structure of the viral capsid and stability. Neutron and X-ray scattering measurements will be carried out to verify and optimize the modeling results. Both theory and scattering experiments will be closely guided by biochemical and genetic studies of HBV morphogenesis and the biophysical investigations will in turn frame future biochemical and genetic approaches to regulate and ultimately eradicate HBV infection.